Vancomycin is an important antibiotic, often prescribed for the treatment of staphylococcal infections or other infections caused by gram-positive bacteria, particularly methicillin-resistant strains of staphylococcus (MRSA). Vancomycin (FIG. 1) degrades in water to a number of products including its predominant degradation products, which are known as vancomycin CDP-1, or CDP-1-M and CDP-1-m (collectively, the CDP-1s) (see Sheldrick et. al., Nature 271:223, 1978, Harris et. al., J. Am. Chem. Sci. 1983, 105, 6915-6922). CDP-1 formation relates to hydrolysis, deamidation and re-arrangement of an asparagine moiety in the vancomycin structure (FIG. 2). CDP-1s are insoluble in water and readily precipitate from solution, rendering the solution unsafe for injection. Although the vancomycin degradation pathways and structures of CDP-1s are well elucidated, there is no available method for inhibiting the CDP-1 formation in water or vancomycin degradation in general. To date, a liquid, aqueous and ready-to-use vancomycin drug product is not available because of the limited stability of vancomycin in water.
Currently, vancomycin is formulated for pharmaceutical use as a dry powder in capsules for oral administration, and as a sterile dry powder filled in vials or as a frozen liquid preparation for parenteral use. The dry powder filled in vials is produced by lyophilization and must be dissolved in water before it can be injected. The frozen liquid needs to be thawed and warmed to room temperature before use. Both forms are costly to manufacture, distribute and store and inconvenient because they are not in ready-to-use formats. Therefore, an aqueous and ready-to-use vancomycin solution formulation is highly desirable. A solution formulation will have reduced manufacturing costs by eliminating the need for lyophilization. Pharmacy time and labor and their costs could be reduced because there will be no need to reconstitute the dry powder nor will there be the need for freezer storage.
A solution prepared from the currently marketed product (i.e. a reconstituted solution from the vancomycin dry powder or a thawed solution from the frozen solution) would fail the impurity and/or particulate matter specifications, as defined by the United States Pharmacopeia for Vancomycin Injection, USP, for in a matter of hours or few days due to the rapid generation of CDP-1s. The formation of CDP-1s is the shelf-life-limiting degradation pathway for vancomycin in water.
Therefore, a solution formulation in which vancomycin is stabilized is desirable. Furthermore, such a stable vancomycin solution formulation enables the development of other dosage forms of vancomycin for topical, ophthalmic, otic, intranasal, instillation or intravaginal routes of administration for use in applications where a ready-to-use solution is typically required.
WO 1997019690 A1 discloses stable solutions of vancomycin hydrochloride comprising between about 0.5% and about 12% w/v vancomycin hydrochloride and between about 0.5% and about 30% v/v ethanol. These solutions are particularly useful for storage in a liquid state not requiring either freezing or freeze drying in order to maintain stability of the active agent. There is no mention of using tryptophan as a stabilizer for vancomycin in this patent.
WO 2014085526 A1 teaches a stabilized, lipid-based glycopeptide antibiotic composition comprising: (a) a lipid component; (b) a glycopeptide antibiotic component; and (c) an amino acid or a derivative thereof, wherein the amino acid or the derivative thereof stabilizes the glycopeptide antibiotic. Exemplary amino acids and amino acid derivatives suitable for the invention include alanine (ALA), D-alanine (D-ALA), alanine-alanine (ALA-ALA), beta-alanine (bALA), alanine-beta-alanine (ALA-bALA), 3-aminobutanoic acid (3-ABA), gamma-aminobutyric acid (GABA), glutamic acid (GLU or GLUt), D-glutamic acid (D-GLU), glycine (GLY), glycylglycine (GLY-GLY), glycine-alanine (GLY-ALA), alanine-glycine (ALA-GLY), aspartic acid (ASP), D-aspartic acid (D-ASP), lysine-alanine-alanine (LYS-ALA-ALA), L˜Lysine-D˜alanine-D˜alanine (L-LYS-D-ALA-D-ALA), lycine, tricine, sarcosine, and iminodiacetic acid (IDAA). There is no mention of using tryptophan as a stabilizer for vancomycin in this patent.
WO 2012159103 A1 discloses a composition comprising vancomycin or a pharmaceutically acceptable salt thereof, wherein the composition is a dry powder, and wherein the composition further comprising a hydrophobic amino acid selected from the group consisting of: tryptophan, tyrosine, leucine, trileucine, and phenylalanine. The inventors stated, “It may be desirable to include a hydrophobic amino acid in a composition of the present disclosure so as to improve the physical stability and/or dispersibility of the composition, improve the chemical stability of vancomycin or a pharmaceutically acceptable salt thereof, and/or to alter the taste of the composition by masking the bitter taste of vancomycin and its salts, and/or to alter the rate the composition is absorbed into the systemic circulation from the lung (e.g., increase or slow the rate). While not wishing to be bound to any particular theory, it is currently believed that the hydrophobic amino acid additive remains on the surface of the particles and protects them from moisture and light, thereby increasing the stability of the formulation.” There is no teaching or suggestion in this patent to use tryptophan as a stabilizer for vancomycin in solution to inhibit CDP-1 formation.
US 20070116649 A1 patent application discloses an aqueous or powder composition that contains an anti-gram-positive antibiotic or salt thereof being present at a concentration ranging from about 0.6 to about 0.9 of the water solubility limit at 25° C. and 1.0 atmosphere, of the anti-gram-positive antibiotic or salt thereof. The anti-gram-positive antibiotics include vancomycin and exemplary excipients as bulking agents, buffers or dispersing agents include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline. According to Merck Index (12th edition), the solubility of vancomycin hydrochloride in water is >10% w/v, therefore, the vancomycin concentration range from about 0.6 to about 0.9 of the vancomycin solubility limit corresponds to >6% to about >9% w/v vancomycin, which is much higher than the vancomycin concentration range (0.1% and about 5% w/v) useful for the current invention.
None of above related art discloses a stable vancomycin solution composition of this invention, nor teaches a method for using tryptophan to stabilize vancomycin in solution. There still is a need for a new vancomycin solution formulation that is aqueous, ready-to-use, injectable and stable for at least 12 months in a non-frozen form.